Diabetes mellitus (DM) is a chronic, debilitating and often fatal endocrine disease characterized by a status of hyperglycaemia and eventual glycosuria, caused by the inability of tissues to carry out normal metabolism of carbohydrates. Two forms of DM are usually described: the insulin dependent DM (type 1) and the non-insulin dependent DM (type 2). The first is characterized by a strong deficiency on insulin secretion, associated with auto-immune destruction of pancreatic β-cells. Type 2 DM is caused by a combination of resistance to insulin and impaired insulin secretion, corresponding to more than 90% of cases.
As a result of the long term hyperglycaemia, severe damage of body systems can occur, especially on nerves, blood vessels, heart, eyes, and kidneys conducing to neuropathies, retinopathies, nephropathies and cardiovascular complications. Due to population growth, aging, urbanization, lifestyle alterations and increasing prevalence of obesity, the last two decades have seen an explosive worldwide increase in people diagnosed with DM. According to the last projections from the International Diabetes Federation (IDF) and World Health Organization (WHO) this disease will affect 380 million people in 2025.
DM is becoming the third “killer” of mankind, along with cancer, cardiovascular and cerebrovascular diseases. Because of its prevalence, the WHO has declared DM as an epidemic disease. Although patients can, in most cases, control their glycaemia with the available therapeutically means, together with a correct nutrition, the research of new and effective medicines for the prevention and treatment of this chronic disease is absolutely needed.
Plant Kingdom is a source of bioactive principles against many health problems and a variety of plant metabolites like saponins, alkaloids, flavonoids, anthraquinones, terpenes, coumarins, phenolics, polysaccharides, etc, and plant extracts from a large number of plant families are claimed to possess antidiabetic properties.
Previous research work [4,5,6,7] was developed by the Carbohydrate Chemistry Group of CQB-FCUL [RG-CHEM-LVT-Lisboa-612-640] on the antidiabetic plant Genista tenera concerning extracts preparation and the identification of its major constituents: alkaloids and flavonoids. The n-butanol extract of flavonoids revealed a promising antidiabetic activity on an experimental animal model. In vitro toxicity studies of this extract showed no evidence for acute cytotoxicity or genotoxicity. The ethanol extract components were studied with the exception of 8-β-D-glucosylgenistein, which is not commercially available. The components apigenin, chrysoeriol and genistein significantly lowered blood glucose levels of STZ induced diabetic Wistar rats. Hence, synthesis of 8-β-D-glucosylgenistein had to be developed. Sato and coworkers have reported the synthesis of this compound starting from 3,5-benzyl protected phloroacetophenone which glucosylation with benzyl protected glucosyl fluoride in the presence of catalytic amount of BF3.OEt2 was followed by aldol condensation with benzyl-protected hydroxybenzaldehyde to give a chalcone. Its oxidative rearrangement with thallium (III) nitrate (TTN) and subsequent acid-catalyzed cyclization and debenzylation led to the final product. However, trials to repeat this synthesis were not successful and the reported yields are not reproducible. In addition, the compound has never been reported to be active against diabetes.
Type 2 diabetes, along with other age-related degenerative diseases including Alzheimer's, Parkinson's and Huntington's diseases is related with the accumulation of amyloid fibrils. This accumulation occurs as an outcome of protein mis-folding and consequent intermolecular hydrogen bonding of extended polypeptide strands. According to Glabe, amyloids from different diseases may share a common pathway for fibril formation, since they share common structural properties mainly determined by their generic polymer properties. Soluble amyloid oligomers showed also evidence to be the primary pathogenic structure, rather than the mature amyloid fibrils.
Type 2 diabetes is characterized by islet amyloid deposits derived from islet amyloid polypeptide (IAPP), a protein co-expressed and secreted with insulin by β-cells, and Alzheimer's disease is characterized by the accumulation of β-amyloid (Aβ) fibrils. Both diseases have genetic components, and both their amyloid fibrils form into amyloid aggregates in an aqueous environment. It has been suggested that there might be a relationship between amyloid deposits in the brain and pancreatic islets. Furthermore, a recent study proved that type 2 diabetes is more prevalent in Alzheimer's disease patients, versus non Alzheimer's disease control patients. Presently there is no report on C-glycosylflavonoids which interact with amyloid oligomers.